Michael addition mediated by an internal catalyst. A novel route to 2-diethylphosphonoalkanoic acids

Article abstract of DOI:10.1055/s-1998-1871

Dicyclohexylammonium 2-diethylphosphonoacrylate reacts readily with a variety of 1,3-dicarbonyl and monocarbonyl pronucleophiles to give the corresponding Michael adducts. Self - catalysis in these reactions is postulated.

Full text of DOI:10.1055/s-1998-1871

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SYNLETT
Michael Addition Mediated by an Internal Catalyst. A Novel Route to 2-Diethyl-
-phosphonoalkanoic Acids
Henryk Krawczyk
Institute of Organic Chemistry, Technical University (Politechnika) 90-924 Lodz, Zeromskiego 116, Poland
Fax: (0-48-42) 636-55-30
Received 22 July 1998
Abstract: Dicyclohexylammonium 2-diethylphosphonoacrylate reacts
readily with variety of 1,3-dicarbonyl and monocarbonyl
The synthesis of phoshonoacrylate 9 from diethylphosphonoacetic acid
7 is outlined in Scheme 2.
a
pronucleophiles to give the corresponding Michael adducts. Self -
catalysis in these reactions is postulated.
Base catalyzed Michael addition of carbon nucleophiles to α,β-
unsaturated carboxylic esters is widely recognized as one of the most
1
important carbon - carbon bond forming reactions in organic synthesis.
In recent years considerable attention has been focused on the use of
various catalysts to effect this reaction under mild and neutral
2
conditions. In spite of impressive progress in this field little effort has
1
been devoted to the Michael reagents that exhibit self-catalytic activity.
We recently described an efficient three-component condensation of
diethylphosphonoacetic acid with formaldehyde and alcohols in the
presence of a catalytic amount of piperidine producing diethyl 1-
3
alkoxymethylvinylphosphonates. We demonstrated that piperidinium
diethylphosphonoacrylate being an intermediate in this condensation
readily reacted as a Michael acceptor with alcohols. This implied that
the conjugate addition of different pronucleophiles to ammonium 2-
diethylphosphonoacrylates 1 should be a new and general route to
ammonium 2-diethylphosphonoalkanoates 6 (Scheme 1).
A
key step in this sequence was the preparation of 9 from
dicyclohexylammonium phosphonoacetate 8 and formaldehyde. It was
found that the use of triethylamine as a catalyst gave the best results.
Thus, the treatment of 8 (1 eq) with triethylamine (1 eq) and excess of
paraformaldehyde (2 eq) in boiling benzene with azeotropic removal of
4
water afforded the solid salt 9 in 70% yield. Although triethylamine
acts as a catalyst it is essential to use it in equimolar amount, otherwise
the final product is accompanied by the unreacted salt 8. One-pot
version of this synthesis has also been accomplished and gave similiar
results concerning purity and the yield of the product. The following
result is also noteworthy: replacing dicyclohexylamine with
diethylamine led to the formation of vinylphosphonate 10 in 87% yield
(Scheme 3). We have already reported the transformation of the acid 7
5
into vinylphosphonates such as 10.
Considering the generally-known basicity of carboxylate anions we
reasoned that proton exchange between the salt 1 and selected CH acids
2
would produce 2-diethylphosphonoacrylic acid
3
and the
Having in hand an efficient method for the synthesis of 9 we performed
a series of Michael reactions using representative C-H pronucleophiles
(Scheme 4).
corresponding carbanions 4. Addition of the anions 4 to the acid 3
would give rise to the formation of the Michael adducts 5 which after
proton transfer would be converted to the final products 6. In this paper
we report our initial studies that validate such a reactivity pattern.
1,3-Dicarbonyl compounds 2a-e, aldehydes 2f and 2g and acetone 2h
were chosen as pronucleophiles. The reactions of 9 with 2a-e proceeded
readily in benzene at room temperature and were completed within two
A crucial issue in the realization of this new paradigm was the choice
and synthesis of a corresponding ammonium phosphonoacrylate 1. We
anticipated that dicyclohexylammonium diethylphosphonoacrylate 9
would be the most appropriate and readily accessible Michael acceptor.
31
6
days ( P NMR) giving the solid salts 11a-e in high yields. In contrast,
monocarbonyl pronucleophiles 2f, 2g and 2h failed to react with 9 at
room temperature. Aldehydes 2f and 2g provided the desired adducts

October 1998
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References and Notes
(1) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon Press: Oxford, 1992.
(2) Nelson, J.H.; Howells, P.N.; DeLullo, G.C.; Landen, G.L.; Henry,
R.A. J. Org. Chem. 1980, 45, 1246. Boyer, J.; Corriu, R.J.P.; Perz,
R.; Reye, C. J. Chem. Soc., Chem. Commun. 1981, 122. Ranu,
B.C.; Bhar, S. Tetrahedron, 1992, 48, 1327. Sreekumar, R.;
Rugmini, P.; Padmakumar, R. Tetrahedron Lett. 1997, 38, 6557.
Subba Rao, Y.V.; De Vos, D.E.; Jacobs, P.A. Angew Chem., Int.
Ed. Engl. 1997, 36, 2661. Kotsuki, H.; Arimura, K. Tetrahedron
Lett. 1997, 38, 7583. Michaud, D.; Texier-Boullet, F.; Hamelin, J.
Tetrahedron Lett. 1997, 38, 7563.
(3) Krawczyk, H. Phosphorus, Sulfur and Silicon, 1996, 113, 39.
(4) Procedure for the preparation of phosphonate 9: A mixture of 8
(37.7g, 0.1mol), paraformaldehyde (6.0g, 0.2mol), triethylamine
(10.1g, 0.1mol) in 200 ml benzene was refluxed for 45 min using
a Dean-Stark apparatus. The solution was filtered to remove the
polymer species and the filtrate was concentrated under vacuum.
The resulting solid was suspended in hexane and filtered. The
crude solid was purified by crystallization from benzene to afford
9 in 70% yield.
o
after heating the benzene solutions at 50 C for 30h. The salt 11h was
o
obtained by heating of 9 in acetone solution at 50 C for 70h. The
phosphonates 11f, 11g and 11h were obtained in moderate yields (70 -
75%). P NMR spectra of the crude products revealed the presence of a
contamination in the vinylphosphonate region (δ 17.9ppm). In an
independent experiment we found that the salt 9 being heated in boiling
benzene decomposed to vinyl phosphonate 13 and dicyclohexylamine.
This might result from decarboxylative elimination of the Michael
adduct 12 as shown in Scheme 5. The structures of the phosphonate 13
31
o
31
1
9: mp. 115-116 C; P NMR (101 MHz, CDCl ): δ 17.58;
H
3
NMR (250 MHz, CDCl ) δ 1.11-1.36 (6H, m), 1.31 (6H, t, J=7.0),
3
1
13
1.42-1.68 (6H, m), 1.78 (4H, m), 2.03 (4H, m), 2.99 (2H, m), 4.14
and the amine were confirmed by H and C NMR spectra of the
obtained mixture.
2
3
(4H, dq, J=7.0), 6.35 (1H, dd, J=2.5,
J
=21.0), 6.70 (1H, dd,
HP
2
3
J=2.5,
J
=46.0). Anal. Calcd for C H NO P: C, 58.59; H,
HP 19 36 5
Ion-exchange chromatography of the salts 11 afforded the
corresponding acids 5 in quantitative yields.
9.31;N, 3.59. Found: C, 58.65; H, 9.37; N, 3.71.
7
(5) Krawczyk, H. Synth. Commun. 1994, 24, 2263.
In summary, the described synthesis constitutes a method of carbon -
carbon bond formation of potential generality equivalent to that of a
conventional Michael reaction and represents a novel methodology for
(6) General procedure for the Michael addition: To a solution of
phosphonate 9 (3.89g, 0.01mol) in dry benzene (30 ml) 2
8
(0.01mol) was added and the mixture was stirred at the given
the preparation of 2-diethylphosphonoalkanoic acids.
31
temperature until completion of the reaction was confirmed by
P
NMR. After the reaction was completed the solvent was
evaporated and the solid residue was suspended in hexane and
collected by filtration. The crude solid was crystallized from
acetone or acetone/methylene chloride to give 11.

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o
31
Analytical data for 11a: mp. 109-110 C; P NMR (101 MHz,
(3H, t, J=7.2), 2.42 (2H, m), 3.09 (1H, ddd, J=4.5, J=10.5,
1
2
CDCl ), δ 27.28; H NMR (250MHz, CDCl ) δ 1.19-1.34 (6H,
m), 1.30 (3H, t, J=7.0), 1.31 (3H, t, J=7.0), 1.42 (4H, m), 1.65
J
=24.5), 3.62 (1H, dd, J=5.5, J=9.8), 3.73 (1H, s), 3.73 (1H, s),
3
3
HP
13
4.19 (4H, m); C NMR (62 MHz, CDCl ) δ 16.22 (CH ), 16.27
3
3
(2H, m), 1.80 (4H, m), 1.96 (4H, m), 2.43 (2H, m), 2.86 (1H, ddd,
(CH ), 25.97 (CH ), 43.15 (d, J=129.3) (CH), 49.48 (d, J=14.6)
3 2
(CH), 52.70 (2xCH ), 63.28 (d, J=6.3) (CH ), 63.67 (d, J=6.5)
3 2
2
J=4.0, J=10.7, J =22.7), 3.00 (2H, m), 3.70 (1H, m), 3.71 (3H,
HP
s), 3.72 (3H, s), 4.13 (4H, m). Anal. Calcd for C
H
NO P: C,
(CH ), 169.18, 170.29.
2
24 44
9
55.31; H, 8.51; N, 2.68. Found: C, 55.44; H, 8.45; N, 2.81.
(8) Coutrot, P.; Ghribi, A. Synthesis, 1986, 661. Minami,
T.;Hirakawa, K.; Koyanagi, S.; Nakamura, S.; Yamaguchi, M. J.
Chem. Soc., Perkin Trans.1, 1990, 2385.
31
(7) Spectral data for 5a: Colourless oil, P NMR (101 MHz, CDCl )
3
1
δ 24.0; H NMR (250 MHz, CDCl ) δ 1.33 (3H, t, J=7.2), 1.34
3